The field of the invention is cell adhesion, particularly selectin mediated cell adhesion, as well as the treatment of disease conditions related thereto.
Selectin mediated binding plays an important and prominent role in a variety of biological processes. Selectins are lectin like cell adhesion molecules that mediate leukocyte-endothelial, leukocyte-leukocyte, leukocyte-platelet, platelet-endothelial and platelet-platelet interactions. One critical biological process in which selectin mediated binding plays a role is the maintenance of immune surveillance.
Maintenance of immune surveillance depends on the constant recirculation of lymphocytes from the blood through the vascular wall into the tissues and eventually back into the blood. Lymphocyte recruitment from the blood into all secondary lymphoid organs (except the spleen) as well as into many sites of chronic inflammation is mediated by a specialized post-capillary venule called a high endothelial venule. These vessels are defined by the distinct, cuboidal morphology of their endothelial cells and their luminal presentation of ligands for the leukocyte adhesion molecule, L-selectin. This lectin-like adhesion molecule is expressed on all classes of leukocytes in the blood and is responsible for the initial tethering and rolling of a leukocyte on the endothelium prior to subsequent integrin mediated firm arrest and transmigration.
Several selectin ligands have, to date, been identified. The L-selectin endothelial ligands in mouse that have been identified are: CD34, GlyCAM-1, MAdCAM-1 and sgp200. In addition, PSGL-1 has been identified as a leukocyte ligand for P-, E-, and L-selectin. Endothelial ligands for L-selectin in humans are still. poorly defined. However, human CD34 has been shown through a variety of assays to have selectin ligand activity.
Although selectin mediated binding events play a critical role in normal physiological processes, disease conditions do exist for which it is desired to regulate or modulate, e.g. limit or prevent, the amount of selectin mediated binding that occurs. Such conditions include: acute or chronic inflammation; autoimmune and related disorders, tissue rejection during transplantation, atherosclerosis, restenosis following angioplasty, damaging thrombotic events, and the like.
As the above conditions all result from selectin mediated binding events, there is great interest in the identification of selectin ligands and the elucidation of the mechanisms underlying such binding events. There is also great interest in the identification of treatment methodologies for these and related disease conditions, as well the identification of active agents for use therein.
As such, there is continued interest in the identification of new selectin ligands and the elucidation of their role(s) in selectin mediated binding events, as well as the development of therapies for disease conditions arising from such binding events.
U.S. Pat. No. 5,705,623 describes a podocalyxin like protein expressed on glomular epithelial cells. Sassetti et al., J. Exp. Med. (Jun. 15, 1998) 187:1965-1975 discloses the role of human PCLP as a selectin ligand. Other references describing podocalyxin and homologues thereof include: Kershaw et al., J. Biol. Chem. (Jun. 20, 1997) 272: 15708-15714; Kershaw et al., J. Biol. Chem. (Dec. 8, 1995) 270: 2943929446; McNagny et al., J. Cell Biol. (Sep. 22, 1997) 138: 1395-1407; and Kerjaschki et al., J. Cell Biol. (1984) 98:1591-1596. Hub and Rot, Am. J. of Pathology (March 1998) 152:749-757 and Middleton et al., Cell. (Oct. 31, 1997) 91:385-395 provide discussions of the role of chemokines in leukocyte trafficking.
References providing background information on L-selectin binding include: Lasky et al., Cell (Jun. 12, 1992) 69:927-938; Baumhueter et al., Science (Oct. 15, 1993) 262: 436-438; Girard and Springer, Immunology Today (1995) 16: 449; Rosen and Bertozzi, Current Opinion in Cell Biology (1994) 6: 663-673; Celi et al., Seminars in Hematology (1997) 34: 327-335; as well as U.S. Pat. No. 5,580,862.
Podocalyxin like proteins having selectin ligand activity (e.g. PCLP, PCLP-2), as well as methods for producing the same, are provided. Also provided are nucleic acid compositions encoding novel polypeptide products with selectin ligand and/or chemokine presenting activity. The subject polypeptide and nucleic acid compositions find use in a variety of applications, including research applications (e.g. in assays designed to elucidate the biological mechanisms of cell adhesion and trafficking), diagnostic applications, and therapeutic agent screening applications, as well as in therapeutic applications. Also provided are methods of treating disease conditions associated with selectin mediated binding events, such as acute and chronic inflammation, autoimmune diseases and related disorders, tissue rejection and the like.